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Lookup NU author(s): Dr Jérémie Nsengimana
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© 2018 European Association of UrologyTesticular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low-frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined] > 0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation. Patient summary: In the largest study of its kind, we sequenced ∼20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors. We sought to discover if there is a major high-penetrance susceptibility gene for testicular germ cell tumour (TGCT) by analysing whole-exome sequencing data for 919 men with TGCT and 1609 cancer-free controls. We found no evidence for the existence of this class of inherited susceptibility to TGCT.
Author(s): Litchfield K, Loveday C, Levy M, Dudakia D, Rapley E, Nsengimana J, Bishop DT, Reid A, Huddart R, Broderick P, Houlston RS, Turnbull C
Publication type: Article
Publication status: Published
Journal: European Urology
Print publication date: 01/06/2018
Online publication date: 09/02/2018
Acceptance date: 22/01/2018
ISSN (print): 0302-2838
ISSN (electronic): 1873-7560
Publisher: Elsevier B.V.
PubMed id: 29433971
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